tbuckley/cabot-search huggingface dataset:
OncoTherad immunotherapy plus platelet rich plasma as potential therapeutic strategy for ovarian cancer: The role of toll-like receptors 2 and 4 signaling pathways.
Authors: Gabriela Oliveira, Bianca Ribeiro de Souza, Juliane Lima Baggio de Paula, Daniel Henrique da Silva Santos, Gabriela Cardoso de Arruda Camargo, Wagner José Fávaro, Nelson Duran
Journal: Journal of Clinical Oncology (2023)

e17602 Background: Ovarian cancer (OC) has the most devastating death rate of gynecological cancers with only 44% of women surviving 5 years after diagnosis. Toll-like receptors (TLRs) signaling can play an important role in the OC treatment. TLR activation in immune cells can help activate an effective antitumor response. In this scenario, a new perspective is represented by combined OncoTherad (MRB-CFI-1) immunotherapy and Platelet Rich Plasma (PRP). OncoTherad (MRB-CFI-1) leads to the distinct stimulation of the innate immune system mediated by TLR2 and TLR4, resulting in an increased activation of the IFN signaling pathway. Also, PRP acts on immune activation and exerts antitumor effects. This study characterized the histopathological and molecular effects of the OncoTherad associated with PRP in the treatment of OC chemically induced in rats and described the possible mechanisms of action of this association involving the TLRs 2 and 4 signaling pathways. Methods: Fischer 344 female rats were divided into 5 groups (n = 7 animals per group): Control (Sham surgery) group; Cancer (7,12 dimethylbenzoanthracene – DMBA injection in the ovarian bursa, 1.25 mg/kg) group; OncoTherad (20mg/kg) group; PRP (328.10 3 – 549.10 3 platelets/mm 3 ) group and; OncoTherad+PRP (same doses of the isolated treatments) group. Intraperitoneal doses were administered twice a week for 4 weeks. Immunohistochemistry was analyzed as total immunoreactivity and intensity of immunoreaction. Results: Our results showed serous type ovarian carcinoma, follicular atresia, absence of corpora lutea and hyperplasia of the germinal epithelium and tunica albuginea in the Cancer group. The histopathological changes in the PRP group were similar as Cancer group. In contrast, the animals treated with OncoTherad singly or in combination with PRP showed decrease of ovarian neoplastic lesions and histopathological recovery. TLR4 and IL-6 immunoreactivities were significantly lower (p &lt; 0.05) in the Cancer group. PRP treatment reduced (p &lt; 0.05) TLR2. In the Oncotherad+PRP group, the immunoreactivities of TLR4, MyD88, IRF-3 and TNF-α were lower. OncoTherad treatment alone led to stimulation of the innate immune system mediated by TLR2 and TLR4, resulting in an increased activation of the MyD88 signaling pathway (intensified IL-6 and TNF-α immunoreactivities). Conclusions: OncoTherad immunotherapy was able to reduce ovarian lesions and stimulated the TLR2 and 4 signaling pathways in the OC microenvironment, leading to antitumor effects by activating the production of inflammatory cytokines. Thus, OncoTherad immunotherapy could be considered an important therapeutic strategy for OC.
Impact of neighborhood disadvantage on stage at diagnosis and outcomes in women diagnosed with breast cancer.
Authors: Alexandra A Harris, Aniko Szabo, Sailaja Kamaraju, Yee Chung Cheng, John D. Burfeind, Christopher R. Chitambar, Lubna Naaz Chaudhary
Journal: Journal of Clinical Oncology (2023)

e18603 Background: Low socioeconomic status (SES) has been associated with higher incidence of high-risk breast cancer and poorer outcomes. However, previous studies have inconsistent definitions of SES. Using a more comprehensive definition of SES via the Neighborhood Atlas, which calculates one's relative level of Neighborhood Disadvantage (ND) using 17 variables from American Community Survey and US Census data, may address this problem. We aimed to determine if higher level of ND is associated with later stage breast cancer at diagnosis and/or higher five-year recurrence rates. Methods: We performed a retrospective chart review study of 418 women that were diagnosed with breast cancer in 2015 within the Froedtert Health System in WI. Data collected included: patient characteristics (age, race, BMI, menopausal status, genetic status), tumor characteristics (tumor size, nodal status, metastases, ER/PR/HER2 status, histology, grade, date of diagnosis, self- detected vs. abnormal mammogram), treatments received (surgery, radiation, chemotherapy, endocrine therapy), and outcomes (type of recurrence, date of recurrence, date of death if applicable, last follow-up, etc.). Patient home addresses at the time of diagnoses were geocoded and inputted into the Neighborhood Atlas Mapping Tool to obtain 2015 ND values. Spearman’s rank correlation was used to evaluate the association between ND and TNM stage at diagnosis. Cox regression was used to evaluate the effect of ND on cause-specific hazard of recurrence. Significance value of &lt; 0.05 was utilized. Results: The average age at diagnosis was 60 years and most women were post-menopausal (74%). Most patients had ER and/or PR-positive cancer (82% and 72% respectively) and 15% had HER2-positive disease. The average tumor size was 1.3cm (range 0-10). Node positive disease was seen in 104 women (25%) and 20 women (4.8%) had distant metastatic disease at diagnosis. Only 24 (5.7%) patients experienced disease recurrence within five years of diagnosis. The average National ND value was 36 (range of 4 to 100). ND was not significantly associated with stage at breast cancer diagnosis (p = 0.37) or five-year recurrence rates (p = 0.19). Conclusions: The average National ND value was not significantly associated with stage at breast cancer diagnosis or five-year recurrence rates. It is important to consider our study population demographics in the context of these results. The average National ND value was low at 36 which suggests an unequal representation of those living in disadvantaged areas compared to those living in more advantaged areas. Additionally, we were unable to draw strong conclusions on effects of ND on patient outcomes due to low number of recurrences seen. Future studies with larger sample size are likely needed to capture the possible impact of ND on patient outcomes.
Multivariate index assay MIA3G vs other assessment tools for the ovarian cancer risk assessment of indeterminate masses.
Authors: Srinka Ghosh, Todd C Pappas, Ryan Phan
Journal: Journal of Clinical Oncology (2023)

e17609 Background: Estimated 10% of women with adnexal masses will undergo preventive surgery for ovary removal to mitigate malignancy risk. This is significant, compared to the 15% rate of ovarian cancer (OC) confirmed by pathology. On the other hand, a women’s lifetime risk of getting OC is estimated at 1 in 78, with death at 1 in 108. This predicament motivates a surveillance paradigm for assessment of malignancy risk. ROMA (Roche) is a multi-marker assay intended to assess the cancer risk of adnexal masses in women already scheduled for surgery. We recently characterized the clinical performance of MIA3G[1], to assess OC risk for women with adnexal mass clinically characterized as benign or indeterminate. Here we present the comparative analysis for MIA3G and ROMA in a multi-site study. Methods: MIA3G -a 7-biomarker assay with a DNN-based risk prediction algorithm – was tested for clinical management of women (median: 51yo, IQR:41-61) across 11 centers. Data is presented for 206 patients with adnexal mass (286 unique samples), who follow an admix of surgical and clinical management. The continuous MIA3G probabilistic scores and dichotomized risk classification were used for the analyses. The primary objective was to compare MIA3G with ROMA assays. The secondary objective was to validate – via a pair-wise approach – the correlation of the biomarkers, age and menopausal status(MENO) - with the predicted risk stratification. Results: MIA3G stratified 13% [CI:0.096-0.174] and 87% [CI:82.6-90.4] of the 286 samples as indeterminate and low risk of malignancy respectively (p-value&lt;2.2e-16, Welch’s t-test). In comparison, ROMA stratified 11.3% with a high likelihood of finding a malignancy on surgery. In the pre-menopausal sub-cohort MIAG3 risk-stratified only 7% as indeterminates, whereas for ROMA and CA125 the analogous estimates increased to 15% and 20% respectively. For the post-menopausal population, the converse trend was observed. In MIAG3 with increasing risk, the inhibitive effect of APO was signaled (R 2 :-24%, p:0.0006) and potential implication of iron metabolism was observed in TFR (R 2 :-31%,p:9.76e-5). B2M indicated inflammation with increasing risk (R 2 :28%, p:0.052. In addition to being a clinical attribute, MENO status was confirmed with FSH and age (R 2 &gt;80%,p&lt;2.2e-16). A strong correlation of risk with HE4 (R 2 :38%) and CA125 (R 2 :32%) was observed and a HE4-CA125 pairwise-correlation of &gt;85% confirmed. Additionally, the positive association of PRE with APO( R 2 :33%) and negative association with CA125 and HE4 (R 2~ :-20%) rounded out the comprehensive nature of the MIA3G assay for characterizing the nuanced evolution of the masses. Conclusions: This real-world study established the efficacy of MIA3G as the most clinically validated tool for the risk assessment of ovarian cancer of indeterminate masses. 1: DOI 10.3389/fmed.2023.1102437.
Treatment of newly developed metastases after definitive chemoradiotherapy +/- ICI for unresectable stage III NSCLC.
Authors: Julian Taugner, Kerstin Hofstetter, Lukas Käsmann, Sophie Kröninger, Sofie Schmidt, Amanda Tufman, Niels Reinmuth, Thomas Duell, Claus Belka, Chukwuka Eze, Farkhad Manapov
Journal: Journal of Clinical Oncology (2023)

e20603 Background: Assessment of salvage treatment for newly developed metastases in patients previously treated with curative-intent concurrent chemoradiation (cCRT) +/- immune checkpoint inhibition (ICI) for unresectable stage III NSCLC. Methods: We analysed data of 136 patients treated from 2011 to 2020 in as single tertiary cancer centre. Location of first observed distant metastasis (DM) were categorized as brain/intracranial metastasis (BM), organ metastasis (OM) and skeletal metastasis (SM). Treatment with radiotherapy (RT) and systemic therapy (ST); sub-divided into chemo- (CT), immuno (IT) and tyrosine kinase inhibitor therapy (TKI) was assessed. Results: All patients received definitive cCRT ≥ 60 Gy with 2 courses of chemotherapy. Thirty-six (26%) patients received ICI. Median follow-up was 49.7 months, median PFS was 9.9 (95%CI: 7.0-12.7) months, 12- and 24-month PFS-rates were 42% and 29%, respectively. Median OS was 31.2 months (95% CI 16.9 – 45.6), 12- und 24-month-OS-rates were 74% und 53%. Sixty-one patients (45%) developed metastasis: 21 (15%) BM, 20 (15%) OM und 20 (15%) SM. Median OS of patients with BM, OM and SM was 27.4, 25.5 and 17.9 months, respectively (p = 0.821). In total 45/61 patients were initially treated with cCRT and 16 with cCRT+ICI. Median OS was 26.5 (cCRT+ICI) vs. 23.4 (cCRT) months (p = 0.121); 12- and 24- month survival rates were 94% vs. 64% and 63% vs. 47%. Patients with SM survived significantly longer, if the initial treatment included ICI (Median not reached vs. 7.5 months; p = 0.042). Fifty-three (87%) of 61 patients received the following salvage therapy: 28 (53%) RT, 10 (19%) ST and 15 (28%) combined RT + ST. Patients with SM showed a trend towards longer OS after RT-alone (p = 0.069). Thirteen patients with adenocarcinoma received ST: 7 CT and 6 TKI with a significant longer OS (40.1 months TKI vs. 12.1 months CT; p = 0.040). All 21 patients with BM were treated with RT. Patients treated with stereotactic radiosurgery (SRS) showed a significant longer OS of 40.1 months vs. 12.2 months for patients treated with whole brain radiotherapy (WBRT) (p = 0.016). Conclusions: Patients with SM had a significantly longer OS if their initial therapy consisted of cCRT+ICI vs. cCRT alone. Patients with BM as first site of metastasis had a significantly longer OS when treated with SRS vs. WBRT. Salvage treatment with TKI resulted in a significantly longer OS compared to salvage CT in patients with adenocarcinomas.
Association of HRD ovarian cancer by RAD51 with hot immune microenvironment: Translational analyses of MITO 16A/MaNGO-OV2 trial.
Authors: Benedetta Pellegrino, Ettore Capoluongo, Nicoletta Campanini, Antonino Musolino, Angelica Sikokis, Chiara Casartelli, Nicola Normanno, Laura Arenare, Violeta Serra, Alba Llop-Guevara, Carmela Nardelli, Luca Beltrame, Daniela Califano, Maurizio D'Incalci, Cristin Roma, Delia Mezzanzanica, Gustavo Baldassarre, Francesco Perrone, Sergio Marchini, Sandro Pignata
Journal: Journal of Clinical Oncology (2023)

5527 Background: Homologous recombination repair (HRR)-deficient Ovarian Cancer (OvC) is sensitive to PARP inhibitors and platinum salts. Genomic HRR-deficiency (HRD) tests (i.e. Myriad MyChoice) are currently used to guide treatment selection in the maintenance setting. However, they are showing a limited predictive value, they are expensive and static, i.e. unable to capture the restoration of the HRR functionality, as a mechanism of drug resistance. Methods: We performed the functional and dynamic RAD51 test on 164 patients with high-grade serious OvC, enrolled in the MITO16A/MANGO OV2 trial and treated with first-line therapy containing carboplatin, paclitaxel, and bevacizumab. The RAD51 assay included the immunofluorescence of gH2AX (as a marker of Double Strand Breaks DNA damage), BRCA1 and RAD51 nuclear foci. Stromal Tumor Infiltrating Lymphocytes (TIL) by Immunohistochemistry, and gene expression profile were performed on the same samples. Results: RAD51 assay was informative on 70% (115/164) of the samples. On evaluable samples, median gH2AX score was 57%. BRCA1 foci by immunofluorescence were detected on 55% (49/112) of the samples; 45% (63/112) of the tumors did not show BRCA1 foci likely due to germline or somatic BRCA1 mutations, or BRCA1 promoter hypermethylation. RAD51 identified 69% (79/115) of all tumors as HRD, with a median RAD51 score of 8.8%. HRD tumors presented a statistically significantly higher TIL content than HRR-proficient ones (p = 0.03). Conclusions: Our preliminary results confirmed the feasibility of the RAD51 functional assay on primary untreated OvC. The association between HRD by RAD51 and TIL content encouraged to investigate the efficacy, in clinical trials, of the combination of PARPi and immune-checkpoint inhibitors on selected patients (i.e. HRD by RAD51 and TIL high). Gene expression profile and comparison of the HRD status by RAD51 and genomic HRD (both Myriad MyChoice and academic) and correlations with clinical outcomes will be available for the meeting.
Prognostic value of insulin-like growth factor receptor 1 (IGF1R) expression in high-grade serous ovarian cancer (HGSOC) treated with first line platinum derivative based chemotherapy.
Authors: Bartosz Szymanowski, Michał Bieńkowski, Rafał Pęksa, Szczepan Cierniak, Renata Duchnowska
Journal: Journal of Clinical Oncology (2023)

e17577 Background: Insulin-like growth factor receptor 1 (IGF1R) expression is frequently observed in ovarian cancer patients. Based on data from the literature, the IGF1(IGF2)/IGF1R pathway may be associated with resistance to platinum derivative based chemotherapy. Methods: The study group included 64 Caucasian women with serous high-grade ovarian cancer (HSOC) stage III-IV TNM/FIGO classification, treated 1 st line platinum derivative based chemotherapy between 2004-2014. The analysis of clinical data was carried out based on data from medical records. IGF1R expression was assessed by immunohistochemistry using the monoclonal antibody Roche Rabbit Monoclonal (G11) in tissues from paraffin-embedded blocks. Progression free survival (PFS) was analyzed as the time from the start of chemotherapy to progression. Overall survival (OS) was defined as the time from diagnosis to the patient's death, regardless of cause, or to the last contact with the patient. In all analyses, the significance level was p = 0.05. Statistical analysis was performed using the 3.4.3 version of R statistical environment. Results: The median follow-up was 1023 days (range 157 to 3420 days). The median PFS was 14.0 (95%CI: 11.9-18.0) months. Median OS was not reached. The average patients age was 62 years (range 37-83). Platinum-sensitivity, partial platinum-sensitivity, platinum resistance and platinum-insensitivity were found in 23 (37.1%), 17 (27.4%), 21 (33.9%) and 1 (1.6%) patients, respectively. Any IGF1R expression was noted in 57 patients with the median H-score of 220 (range: 0-300; IQR: 100-207). Median PFS for IGF1R H-score 220 and IGF1R &gt; 220 was 15.4 (95% CI: 13.1-23.3) and 10.8 (95% CI: 9.6-NA) months, respectively. In multivariate analysis PFS was associated with the extent of surgery: cytoreduction secondary vs. primary (WR = 1.94; p = 0.03), suboptimal vs. optimal (WR = 2.16; p = 0.01), body mass index (WR = 0.44; p = 0.05) and IGF1R expression ( &gt; 220) (WR = 2.84; p = 0.04). Conclusions: High expression of IGF1R (H-score &gt; 220) in stage III/IV HGSOC patients treated in 1 st line platinum derivative-based chemotherapy is a negative prognostic factor.
Investigating the association between <i>BRCA1/2</i> copy number variation and homologous recombination deficiency score in ovarian cancer: A cross-sectional study.
Authors: Liufeng Yang, Yuanyue Li, Qian Hu, Tingting Zhang, Mengyue Cui, Jie Zhang
Journal: Journal of Clinical Oncology (2023)

e17584 Background: PARP inhibitors (PARPi) have shown significant clinical benefit as maintenance or systematic therapy in patients with ovarian cancer (OC) with BRCA1/2 mutation or positive homologous-recombination deficiency (HRD) status. However, patients with BRCA1/2 mutation not only showed better efficiency of PARPi, but also higher HRD score than other populations. Therefore, patients with BRCA1/2 mutation have received much attention. However, there are many kinds of variants in BRCA1/2 of OC patients. The purpose of this study is to explore the distribution of BRCA1/2 copy number variation (CNV) in OC patients and its association with HRD score. Methods: A cross-sectional analysis of 1636 OC patient who were retrospectively analyzed with a customized 3D-HRD panel (panel of Next-generation sequencing) between 2020 and 2022 was carried out. The HRD score was calculated as the sum of the LOH, TAI, and LST and we defined HRD score more than 30 and deleterious BRCA1/2 mutation as HRD positivity. Results: In this cohort (n = 1636), we divided the patients into 4 groups according to the BRCA1/2 status. Group1: patients with BRCA1/2 SNV (single-nucleotide variation) combined with CNV (n = 45); Group2: patient with BRCA1/2 CNV (n = 155); Group3: patient with BRCA1/2 SNV (N = 308); Group4: patient with BRCA1/2 WT (wild type, n = 1128). HRD scores decreased significantly from Group1 to Group4. And the proportion of HRD positive patients decreased significantly from Group1 to Group4. Conclusions: Different BRCA1/2 statuses lead to different HRD characterization in OC patients. OC patients with BRCA1/2 CNV (with/without BRCA1/2 SNV) showed higher HRD score than patients with BRCA1/2 SNV. These patients may deserve opportunity for PARPi treatment besides patients with germline or somatic BRCA1/2 mutation, especially for PARPi with specific requirements for patients, such as Olaparib.
Understanding testing for and treatment of homologous recombination repair (HRR)-mutated metastatic castrate-resistant prostate cancer (mCRPC): A quality initiative by Integra Connect (IC) PrecisionQ.
Authors: Roby Antony Thomas, Mike Gart, Simon Blanc, Rushir J. Choksi
Journal: Journal of Clinical Oncology (2023)

e17052 Background: In May of 2020, the approval of two Poly (ADP-ribose) polymerase inhibitors (PARPi) changed the landscape for treatment among patients (pts) with HRR mutations (HRRm) in mCRPC. The University of Pittsburgh Medical Center (UPMC) conducted a quality initiative (QI) with IC PrecisionQ to assess the rates of HRR testing, HRR positivity, and study the rates of PARPi use in HRRm patients with mCRPC. This QI included clinical interventions to optimize testing and treatment in these patients. We aim to show the improvement in HRR testing and rates of treatment with PARPi after implementation of the QI, in patients with HRRm mCRPC at UPMC. Methods: Using the de-identified IC PrecisionQ database, 223 UPMC pts with mCRPC were selected by medical chart curation as baseline group. Patients in the baseline group had received treatment between 5/1/2020 to 9/30/2021 that were confirmed as mCRPC. The baseline data was reviewed with UPMC clinical leadership, discussed among a physician roundtable, and HRR testing rates were shared among providers. Post-baseline, we evaluated 152 mCRPC pts who started a new line of therapy between 1/1/2022 to 12/31/2022 to assess HRR testing rates and use of PARPi in eligible mCRPC pts. The presence of one or more HRR genes was used to determine testing rates. Descriptive analyses were performed and a two-proportion z-test was used for comparisons of HRR testing in patients with mCRPC and treatment with a PARPi in HRRm mCRPC pts. Results: The average age at diagnosis was 67 years, 47% of patients had a Gleason score of &gt; = 8, and 62% were stage IV. The rate of HRR testing at baseline was 52% (116 of 223). The results post baseline and intervention showed an increase in HRR testing to 69% (105 of 152) of mCRPC patients who started a new line of therapy in 2022 (p &lt; 0.01). At baseline, 60% (21 of 35) of HRRm pts were treated with a PARPi after prior NHA treatment compared to 68% (19 of 28) post baseline and intervention (p &gt; 0.05). Among all HRR mCRPC tested pts, there was a 30.9% (84/272) positivity rate, of which 11.4% were BRCA1/2 positive (30/262) and 10.5% were ATM positive (26/247). Not all patients tested for HRR were tested for all genes. Conclusions: This quality initiative to improve testing and identification of HRR mutations in patients with mCRPC led to a 33% relative increase in HRR testing. Quality initiative programs are critical to transforming cancer care and moving the field closer toward individualized, precision medicine.